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I got the following today from the Auto-Immune Digest:
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Authors and Disclosures

Journalist

Allison Gandey

Allison Gandey is a journalist for Medscape. She is the former science affairs analyst for the Canadian Medical Association Journal. Allison, who has a master of journalism specializing in science from Carleton University, has edited a variety of medical association publications and has worked in radio and television. She can be contacted at agandey@webmd.net.

From Medscape Medical News

On the Congress Floor: Specialists Debate New Oral Agents for MS

Allison Gandey

October 29, 2010 (Gothenburg, Sweden) — The first oral treatment for multiple sclerosis (MS) is entering the market and is changing the prescribing landscape. Many specialists anticipate an excited push by patients to trade injections for tablets, yet many remain wary of the long-term safety and say they will be slow to switch patients.

During a news conference here at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, Jon Lycke, MD, from Sahlgrenska University in Sweden, told reporters that he plans to leave his patients, who are on injections and doing well, on their current standard medications.

"Tablets are much easier and more convenient for patients, so I think there will be an urge by some to switch, but we still have a long way to go, and I'd like my patients who are doing well to remain on their injections," he says.

Dr. David Kupfer
Ludwig Kappos, MD, from University Hospital in Basel, Switzerland, told reporters that although new options are exciting, the decision-making process isn't getting any easier. "There are advantages and disadvantages, and we will have to weigh these carefully against the evolving side effect profile of new drugs."

In a Medscape expert video commentary, Andrew Wilner, MD, from Lawrence and Memorial Hospital in New London, Connecticut, said, "This is a total game changer." There's no question, he added, that the biggest news at this meeting is the new drugs that are available for the treatment of MS.

Fingolimod (Gilenya, Novartis) is the first oral agent approved in the United States. It acts as a superagonist to sphingosine-1-phosphate receptors on the surface of thymocytes and lymphocytes, reducing the overall number of circulating lymphocytes available to mount an autoimmune reaction to the myelin sheath surrounding axons in MS.

Novartis announced earlier this month the average annual cost of fingolimod will be US $48,000.

Cladribine (Merck Serono) was also in the race for first oral agent for the treatment of MS. Although the drug was previously granted fast-track status by the US Food and Drug Administration in 2006, the agency refused to file the company's new drug application in 2009 amid speculation about tabulation errors and potential safety concerns. Cladribine was recently approved in Russia and Australia but received a negative opinion from European regulators in September, a decision the company plans to appeal.

Other oral MS treatments in development include laquinimod (Teva), teriflunomide (Sanofi-Aventis), and BG-12 (Biogen).

This is a total game changer.

During an interview with Medscape Medical News, Stanley Cohan, MD, medical director at the Providence Multiple Sclerosis Center in Portland, Oregon, said he also plans to leave most of his patients on injections. "I definitely won't consider fingolimod a first-line agent," he said.

"It is very unclear at this point when people should be started on this drug," Dr. Wilner agreed. "It has an annualized relapse rate approximately half that of the interferons."

Sidney Spector, MD, from the Veterans Affairs Medical in Phoenix, Arizona, said that he doesn't believe fingolimod provides any great benefit. "Convenience is the main advantage for the patient," he suggested. "Some people will demand it, but this will have to be weighed carefully against the adverse events. I think many neurologists will choose to wait and see."

Enthusiasm Tempered by Vigilance

Enthusiasm, Dr. Spector added, should be tempered by vigilance about the potential risks of the new immunomodulator.

These concerns were echoed In September at the American Neurological Association annual meeting. Peter Calabresi, MD, a FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) trial investigator, acknowledged the strong efficacy numbers for fingolimod but also its safety signals.

Dr. Calabresi from Johns Hopkins in Baltimore, Maryland, worked on the original 2-year trial. He is now leading the 5-year safety study, which is anticipated to include about 6000 patients.

Patients will have to be closely monitored.

"My personal feeling is that physicians should have access to this drug, but patients will have to be closely monitored," he said during an interview. "I am concerned about the dermatological effects, malignancies, and infections."

In another recent trial of fingolimod, 2 patients died of herpetic infections. The Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) showed a benefit with fingolimod against interferon beta and against placebo, but the adverse events were significant. One patient died of disseminated primary varicella zoster and another of herpes simplex encephalitis.

One problem, Dr. Calabresi said, is that neurologists may not feel entirely equipped to closely monitor the entire body to assess complications of the skin, cancers, and infections. Still, he says, "If you prescribe it, you're responsible for it." And he calls on clinicians to remain vigilant.

Clinical trials of fingolimod were supported by Novartis Pharmaceuticals. Dr. Calabresi has received financial support from the company. The other commentators have disclosed no relevant financial relationships.

26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). October 13-16, 2010.

Since when did neurologists start worrying about side effects of anything they prescribed? Not long ago (cusp of the 1970s or later) they were irrigating the spines of 'MS' patients (a surgical procedure, with, I'm sure, it's own set of difficulties). Maybe they have started to become afraid of lawsuits, or even their own ignorance of the true nature of the disease we (the patients) have come to love. I think one of the untold, unmeasured, and rarely-seen side effects of Interferon treatment is dependence, with a vicious twist: I believe that I was doing as well as one ever can on Rebif, and when I stopped using ths treatment (my own initiative), immune-related symptoms returned far worse than they would have been had I never started. I know, "natural disease course" is the automatic reply. Maybe the Interferons had my CCSVI in check. Bottom line: nobody knows. I bet some are afraid of what will happen when they switch people to an oral drug, precisely *because* nobody knows what the Interferons are doing for them, or to them. Maybe people actually need some kind of prophylaxis because they are stopping Interferons. Bottom line: nobody knows. Certainly these oral drugs have not been tested in the presence of Interferons, because the original thought about PML was that it was limited to those patients on the combination of Tysabri and Avonex. So I'm sure exclusion criteria included taking Interferon.

And perhaps they are concerned because people have started questioning the wisdom of prescribing Tysabri, a substance that prevents the ingress of cellular responders when a reinfection by the JCV occurs. Other people. Patients, even.

I think anythng (including FTY720) which prevents the immune cells from entering the CNS is a double-edged sword which can be harmful in its own way.

"Both studies found that the lower dose of the drug was better tolerated. A small number of serious infections occurred, including two deaths from herpes infections in these studies. And, there appeared to be a higher incidence of cancer in people taking Gilenya."

Hey I thought you encouraged people to take risks? Thanks for staying on top of the safety issues related to MS drugs. I guess the only option left is to get liberated, right?

I think it's notable that the two patients who died, died of a latent herpetic infection. Given the strong link between EBV virus antigens and MS, this shouldn't come as a surprise.

To me this is the missing link in CCSVI theory in that the abnormal brain blood drainage is assisting these well-intentioned little devils in harming our myelin.

I happen to think that Liberation + a CRAB to be a good combined strategy. Unfortunately, these drugs are a blunt instrument and I am hesitant to take them - especially the new pill. Hopefully they will make a more precise instrument in the future.

Jugular wrote:I think it's notable that the two patients who died, died of a latent herpetic infection. Given the strong link between EBV virus antigens and MS, this shouldn't come as a surprise.

To me this is the missing link in CCSVI theory in that the abnormal brain blood drainage is assisting these well-intentioned little devils in harming our myelin.

I happen to think that Liberation + a CRAB to be a good combined strategy. Unfortunately, these drugs are a blunt instrument and I am hesitant to take them - especially the new pill. Hopefully they will make a more precise instrument in the future.In the meantime, find a way to remyelinate us!

I believe immune problems and immune-related inflammation occur in CCSVI, and that CCSVI is sometimes the cause of them. I think Jugular is right about the instruments being too blunt; nobody knows exactly what the immune system is reacting to, when it does: maybe blood, maybe flow, maybe a host of things -- or why Interferons have any effect, if they even do.

Fingolimod appears to have an appreciable effect, however it is another attempt to control the immune system by keeping it out of the CNS. It has a history, as it was derived from a Chinese 'nostrum', but I doubt traditional Chinese doctors ever wanted their patients to be on it for life, or to pay their first born child for it.

CCSVI can be an explanation of what triggers the immune system, and it may be mixed up with pathogens, or there may be no conventional ones, but it's kind of like admitting Israel has a right to exist: if we can never get past the 'Zamboni is a quack' nonsense, the clues will be ignored.

I do not blame my neurologist for the tribulations I have suffered. I am a big boy, and I took Interferon (and stopped taking it) after reading about it a lot, just like I did with Liberation. I have been known to read books too; not just the Internet. I guess I must be very old-fashioned that way. Some (repeat, some) neurologists could use some humility, which is very different from humiliation.

I think we have been willing to take anything that has been tested, even some that never have, because it is not very pleasant having 'MS' and we have trusted the 'experts' with our lives. In Canada, some 'experts' have let us down, big time.

I know this topic is off-topic or off-forum. I just thought it was interesting, but I forgot where I was. Mea culpa.

I believe patients will decide for themselves. And MS patients in general seem to be a smart group. There are certain things to consider BEFORE you decide........

Both of the new oral drugs are designed and developed assuming an AUTO IMMUNE (which is different from an hyper-active immune system) cause of MS.

1.They both work similarly causing depression of circulating lymphocytes (I believe one drug corrals the lymphocytes into the lymph glands (not letting them get into the circulating blood) and the other decreases lymphocyte production. The (WBCs) White Blood Cells are the army that fights invaders, add in tissue repair, and healing. 1/3 of all of your WBC army are the Lymphocytes (a specific sub-group). So while you are on one of these drugs you will be considered "Immune Compromised". Advised to stay away from buses, subways, malls, parks, small children, etc. Please learn the role of lymphocytes in the body before you make your decision. Even after stopping the pills the immune system is not normalized for 3 weeks. ( this is quite a long time if you have an infection or injury.

2. The Side effects: Before you decide, read the product information sheets. You can get this from the Physician, the Pharmacist, the Internet ( google: Name of drug and the words "Product Information sheet". They are required by the FDA to provide this to all patients. Look at all of the statistics. Know the definitions to all of the medical terminology.

3. Price ( do I have to say more?)

And IF you believe in the CCSVI theory the WBCs are increased because they are overactively removing debris. The immune system is possibly activated by damaged myelin done by chronic hypoxemia, reflux (shear stress), iron deposition, etc. The over active immune system may be just doing its job as its been signaled that damage has occurred- (not that the Immune cells did the damage).

So I guess one must really know what they believe is happening and remember that all of the pwMS that tested these new oral drugs were NOT people that had angioplasty.

1eye, I think it's completely relevant to discuss fingolimod in this forum. We have to decide what risks to take in light of CCSVI theory.

MegansMom wrote:1.They both work similarly causing depression of circulating lymphocytes (I believe one drug corrals the lymphocytes into the lymph glands (not letting them get into the circulating blood) and the other decreases lymphocyte production. The (WBCs) White Blood Cells are the army that fights invaders, add in tissue repair, and healing. 1/3 of all of your WBC army are the Lymphocytes (a specific sub-group). So while you are on one of these drugs you will be considered "Immune Compromised". Advised to stay away from buses, subways, malls, parks, small children, etc. Please learn the role of lymphocytes in the body before you make your decision. Even after stopping the pills the immune system is not normalized for 3 weeks. ( this is quite a long time if you have an infection or injury.

Scary stuff, MM.

My neurologist specifically thinks fingolimod has too high of side-effects and risk at my stage of MS.

So I guess one must really know what they believe is happening and remember that all of the pwMS that tested these new oral drugs were NOT people that had angioplasty.

You made this point once before and I think it is important to keep making this point. It's a good one.

Don't know if this is the place to debate this or not, but fingolimod does appear to pose a higher risk to its users than other selectively immunosuppressive drugs, such as Tysabri or Rituxan.

While Tysabri keeps T cells out of the CNS, it still allows them the freedom to roam the rest of the body, doing the work that they were evolved to do. Fingolimod keeps them locked in the lymphatic system, so they have no access to the rest of the body. In effect, it's like keeping the police locked in the precinct.

That said, the drug does appear to significantly cut down on relapses and enhancing lesions. Interestingly enough, there are strong indications that the drug might have neuroprotective properties, and is currently undergoing trials on PPMS patients at Johns Hopkins, for that very reason. Neuroprotection is one of the holy grails of MS research, so this drug is definitely a mixed bag.

Just an interesting piece of trivia, the drug is derived from an ancient Chinese herbal remedy called cordyceps, which is a fungus that grows on the back of caterpillars. You can buy cordyceps from online vitamin and herbal supplement retailers. Not sure what part of cordyceps was synthesized, patented, and renamed fingolimod (or Gylenia, the name it will be marketed under). Not even sure it was synthesized, the drug might simply be a refined version of the original (cordyceps).

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